It is well recognized that there are sex-related differences in the incidence and manifestation of heart disease that can not be explained by risk factors alone. For example, men experience higher incidence of congestive heart failure and of persons who do develop congestive heart failure, men are more likely to show evidence of systolic failure, whereas women more frequently have diastolic dysfunction. The lower rate of heart disease-associated morbidity and mortality in females is lost after menopause suggesting that the female advantage may be influenced by sex hormones. As sex hormones act at the molecular/cellular level by altering gene expression, it is reasonably speculated that the mechanism of gender-related differences in heart disease occurs at the cellular level. However, almost no physiologic data is available to explain the cellular basis for these sex-related differences. Using rat left atria as a model, preliminary data from my laboratory demonstrates clear differences in cardiac function between males and females. The primary finding is that female atria generate greater force and have a faster rate of rise and fall in force development than male atria. There are 2 ways that the heart can increase contractile force. One is by increasing the amount of activator Ca2+ delivered to the contractile proteins (myofibrils) and the other is to increase myofibrillar responsiveness to Ca2+. The overall goal of this proposal is to determine whether there is a sex difference in Ca2+ delivery or Ca2+ responsiveness (or both) that can explain the functional difference in force development between atria from male and female hearts. Isolated atrial myocytes will be used to examine the relationship between peak Ca2+ transient and peak shortening, to measure Ca2+ influx across the sarcolemma in cells where the contribution to the Ca2+ transient by the sarcoplasmic reticulum (SR) has been eliminated, and to assess the relative amount of SR releasable Ca2+. Skinned atrial fibers and isolated myofibrils will be used to directly evaluate Ca2+ responsiveness of the contractile proteins. These measures will be compared between males and females. Results of this and future studies will direct differential therapeutic strategies for men and women with cardiac dysfunction.